Contents

Based on receptor binding studies, three variants of the κ-opioid receptor designated κ1, κ2, and κ3 have been characterized.[3][4] However only one cDNA clone has been identified,[5] hence these receptor subtypes likely arise from interaction of one κ-opioid receptor protein with other membrane associated proteins.[6]

It has long been understood that kappa-opioid receptor agonists are dysphoric[15] but dysphoria from kappa opioids has been shown to differ between sexes[16][17]. More recent studies have shown the aversive properties in a variety of ways[18] and the kappa receptor has been strongly implicated as an integral neurochemical component of addiction and the remission thereof.

It is now widely accepted that κ-opioid receptor (partial) agonists have hallucinogenic ("psychotomimetic") effects, as exemplified by salvinorin A. These effects are generally undesirable in medicinal drugs and could have had frightening or disturbing effects in the tested humans. It is thought that the hallucinogenic effects of drugs such as butorphanol, nalbuphine, and pentazocine serve to limit their opiate abuse potential. In the case of salvinorin A, a structurally novel neoclerodanediterpene κ-opioid receptor agonist, these hallucinogenic effects are sought after. While salvinorin A is considered a hallucinogen, its effects are qualitatively different than those produced by the classical psychedelic hallucinogens such as LSD or mescaline.[13]

The involvement of the kappa-opioid receptor in stress response has been elucidated.[15]

Activation of the κ-opioid receptor appears to antagonize many of the effects of the μ opioid receptor.[19]

Kappa opioids have recently been investigated for their therapeutic potential in the treatment of addiction[22] and evidence points towards dynorphin, the endogenous kappa agonist, to be the body's natural addiction control mechanism.[23] Childhood stress/abuse is a well known predictor of drug abuse and is reflected in alterations of the mu and kappa opioid systems.[24]
The area of the brain most strongly associated with addiction is the nucleus accumbens (NAcc) and striatum while some of the surrounding structures also play an important role. Though many other changes occur, most commonly addiction is characterized by the reduction of dopamine D2 receptors in the NAcc.[25] In addition to low NAcc D2 binding,[26][27]cocaine is also known to produce a variety of changes to the primate brain such as increases prodynorphin mRNA in caudate patumen (striatum) and decreases of the same in the hypothalamus while the administration of a kappa agonist produced an opposite effect thereby causing the "healing" effect of increased D2 receptors in the NAcc.[28]

Additionally, while cocaine overdose victims showed a large increase in kappa receptors (doubled) in the NAcc,[29] kappa opioid agonist administration is shown to be effective in decreasing cocaine seeking and self-administration.[30] Furthermore, while cocaine abuse is associated with lowered prolactin response,[31] kappa opioid activation causes a release in prolactin,[32] a hormone known for its important role in learning, neuronal plasticity and myelination.[33]

Though cocaine abuse is a frequently used model of addiction, kappa opioids have very marked effects on all types of addiction including alcohol and opiate abuse.[18] Not only are genetic differences in dynorphin receptor expression a marker for alchohol dependance, but a single dose of a kappa opioid antagonist markedly increased alcohol consumption in lab animals.[34] There are numerous studies which reflect a reduction in self-administration of alchohol,[35]and heroin dependance has also been shown to be effectively treated with kappa agonism by reducing the immediate rewarding effects[36] and by causing the curative effect of up-regulation of mu-opioid receptors[37] which have been down-regulated during opioid abuse.

The deleterious behavioral effects of addiction may be, in part, through the modulatory role D2 receptors of the NAcc play in acetylcholine release in the prefrontal cortex (PFC).[38] Because D2 agonism negatively modulates acetylcholine function in the PFC, extreme central cholinergic function may result from the lower D2 binding rates found in addiction. High cholinergic function of the PFC is associated with mental disorders such as schizophrenia, and high function of these neurons may result in excitotoxicity in areas important for executive function(long-term goal-oriented behavior).[39]

The anti-addictive properties of kappa opioid agonists are mediated through both long-term and short-term effects. The immediate effect of kappa agonism leads to reduction of dopamine release in the NAcc during self administration of an addictive substance[40] and over the long term up-regulates receptors which have been down-regulated during substance abuse such as mu-opioid and D2 (dopamine) receptors. These receptors modulate the release of other neurochemicals such as serotoninin the case of mu-opioids and acetylcholine in the case of d2. These changes can account for the physical and psychological remission of the pathology of addiction. Additionally, the release of prolactin which is characteristic of kappa agonism may be an integral part of overcoming the psychological and behavioral aspects of addiction.

Cannabis sativa: The active component of cannabis, THC, is a partial kappa-opioid agonist and may account for the aversive affects of "paranoia" experienced during its use as well as the counter-intuitive non-addictive properties of cannabis.[43][44]

Ibogaine: Used successfully for the treatment of addiction in most developed countries other than the US, ibogaine has become an icon of addiction management but can be dangerous or fatal. Ibogaine is also a kappa opioid agonist[45] and the information surrounding kappa agonism may prove to be a large portion of the drug's efficacy.

↑Walker BM, Koob GF (February 2008). Pharmacological evidence for a motivational role of kappa-opioid systems in ethanol dependence. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology33 (3): 643–52.